Andrea B. Castro, PhD, CRI-Bristol Myers Squibb Postdoctoral Fellow University College London Though cancer is unique between patients, all tumors share certain hallmarks, including immune evasion. Tumors face pressure to evade immune elimination. Immunotherapies, like checkpoint inhibition (CPI), can help eliminate tumor cells. These immunotherapies are promising, however, not all patients respond. Tumors with high tumor-mutation-burden (TMB) typically have the highest CPI response rates. However, many adult and pediatric patients have low-TMB tumors. TMB is correlated with the number of immune-targetable mutations, however, unexpectedly, >50% of high-TMB patients don’t respond to CPI. The majority of actual CPI responders lack high-TMB despite low-TMB status being one of the strongest correlates to poor outcome. This raises the question: What then is driving response in such patients? The FDA recently approved TMB as a predictor of CPI response, though TMB is poor at stratifying outcome. TMB calculation doesn’t include certain mutations/alterations that are understudied, like from tumor-associated bacteria and dysregulated cellular processes. Dr. Castro hypothesizes that immune-targets from these are associated with CPI response. Tumor bacteria and dysregulation occur frequently and can drive cancer. Furthermore, overlap of immune-targets between patients could be exploited for cost-efficient treatment. There has been no systematic quantification or validation of these immune-targets, partially due to their complexity and lack of large-scale datasets to identify association with CPI benefit. Dr. Castro’s proposed project will comprehensively characterize nonclassical mutations from cancer-associated bacteria and dysregulated cellular processes. This will ultimately help identify key tumor characteristics that are required for response to treatment and how cancer dysregulation shapes the landscape of immune-targetable mutations. Dr. Castro is supported by the CRI Irvington Postdoctoral Fellowship to Promote Racial Diversity. Projects and Grants Investigation of non-classical sources of tumor-specific antigen University College London | All Cancers | 2022 | Kevin Litchfield, Ph.D.
